bims-stacyt Biomed news
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒01‒06
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Diabetol Int. 2017 Aug;8(3): 257-267
    Ota T.
      The immune response and metabolic regulation are highly integrated, and their interface maintains a homeostatic system. Their dysfunction can cause obesity and its comorbidities, including insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). Endoplasmic reticulum (ER) stress is a central abnormality linking obesity, insulin resistance, and NAFLD. ER stress in response to increased hepatic lipids may decrease the ability of the liver to secrete triglyceride by limiting apolipoprotein B secretion, thereby worsening fatty liver. Overnutrition or obesity activates the innate immune system, with the subsequent recruitment of immune cells that contributes to the development of insulin resistance. A significant advance in our understanding of obesity-induced inflammation and insulin resistance has been a recognition of the critical role of adipose tissue macrophages. A role for chemokines, small proteins that direct the trafficking of immune cells to sites of inflammation, has also been demonstrated. Chemokines activate the production of inflammatory cytokines through specific chemokine receptors. This review highlights the chemokine systems linking obesity to inflammation and insulin resistance. Treatment options that target immune cells with the aim of halting the development of insulin resistance and type 2 diabetes remain limited. DPP-4 inhibitors or micronutrients may contribute to the immune regulation of glucose and lipid metabolism by regulating macrophage polarization, thereby reducing insulin resistance and preventing the progression of NAFLD. A detailed understanding of the immune regulation of glucose and lipid homeostasis can lead to the development of a novel therapy for insulin resistance, type 2 diabetes, and NAFLD.
    Keywords:  Chemokine; Dipeptidyl peptidase-4; Endoplasmic reticulum stress; Insulin resistance; Macrophage; Nonalcoholic fatty liver disease
  2. J Biol Chem. 2019 Jan 04. pii: jbc.RA118.005761. [Epub ahead of print]
    Liu Z, Li C, Kang N, Malhi H, Shah VH, Maiers JL.
      Transforming growth factor β (TGFβ) potently activates hepatic stellate cells (HSCs), which promotes production and secretion of extracellular matrix (ECM) proteins and hepatic fibrogenesis. Increased ECM synthesis and secretion in response to TGFβ is associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). TGFβ and UPR signaling pathways are tightly intertwined during HSC activation, but the regulatory mechanism that connects these two pathways is poorly understood. Here, we found that TGFβ treatment of immortalized HSCs (i.e. LX-2 cells) induces phosphorylation of the UPR sensor inositol-requiring enzyme 1α (IRE1α) in a SMAD2/3-procollagen I-dependent manner. We further show that IRE1α mediates HSC activation downstream of TGFβ and that its role depends on activation of a signaling cascade involving apoptosis signaling kinase 1 (ASK1) and c-Jun N-terminal Kinase (JNK). ASK1-JNK signaling promoted phosphorylation of the UPR-associated transcription factor CCAAT/enhancer binding protein β (c/EBPβ), which is crucial for TGFβ- or IRE1α-mediated LX-2 activation. Pharmacological inhibition of c/EBPβ expression with the antiviral drug adefovir dipivoxil attenuated TGFβ-mediated activation of LX-2 or primary rat HSCs in vitro and hepatic fibrogenesis in vivo. Finally, we identified a critical relationship between c/EBPβ and the transcriptional regulator p300 during HSC activation. p300 knockdown disrupted TGFβ- or UPR-induced HSC activation, and pharmacological inhibition of the c/EBPβ-p300 complex decreased TGFβ-induced HSC activation. These results indicate that TGFβ-induced IRE1α signaling is critical for HSC activation through a c/EBPβ-p300-dependent mechanism and suggest c/EBPβ as a druggable target for managing fibrosis.
    Keywords:  IRE1α; adefovir divipoxil; apoptosis signal-regulating kinase 1 (ASK1); c-Jun N-terminal kinase (JNK); c/EBPβ; cell signaling; collagen; endoplasmic reticulum stress (ER stress); fibronectin; fibrosis; p300
  3. Exp Anim. 2019 Jan 01.
    Li S, Yang H, Chen X.
      Sulforaphane (SFN) is abundant in cruciferous plants, providing significant protection against many chronic diseases. With the aim of clarifying the efficacy of sulforaphane in diabetic retinopathy (DR), a series of systematic studies were carried out in the present study. Male Sprague Dawley rats were intraperitoneally injected with streptozotocin (STZ, 65 mg/kg), and those with confirmed diabetes mellitus were given different doses of SFN (0.5 and 1 mg/kg/d) for 12 weeks. In vitro, Müller cells exposed to 25 mM glucose were treated with 2.5 μM SFN. The results indicated that SFN significantly reduced the generation of pro-inflammatory cytokines (TNF-α,IL-6, and IL-1β) and enhanced the activity of antioxidant enzymes (GSH, SOD, and CAT) in the retina of STZ rats. Further, SFN enhanced the nuclear accumulation of Nrf2 and increased the expression of HO-1 and NQO1, two major antioxidants downstream to Nrf2, in the injured retina. In addition, retinal expression levels of NLRP3, cleaved caspase-1 p20, IL-1β p17, and ASC were dramatically increased in STZ-induced DR, and this was abolished by SFN intervention. In vitro, high glucose-induced inflammation and oxidative stress damage in Müller cells were attenuated by SFN. SFN also exerted antioxidant effects, activated the Nrf2 pathway, and inhibited the NLRP3 inflammasome in Müller cells. In conclusion, our work demonstrates that SFN attenuates retinal inflammation and oxidative stress induced by high glucose and activates the antioxidative Nrf2 pathway and inhibits the formation of the NLRP3 inflammasome in vivo and in vitro.
    Keywords:  Nrf2 signaling pathway; diabetic retinopathy; inflammasome; oxidative stress; sulforaphane
  4. Cell Metab. 2018 Dec 20. pii: S1550-4131(18)30741-1. [Epub ahead of print]
    Zhang S, Weinberg S, DeBerge M, Gainullina A, Schipma M, Kinchen JM, Ben-Sahra I, Gius DR, Charvet LY, Chandel NS, Schumacker PT, Thorp EB.
      During wound injury, efferocytosis fills the macrophage with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to how metabolic phagocytic signaling regulates the signature anti-inflammatory macrophage response. Here we report the metabolome of activated macrophages during efferocytosis to reveal an interleukin-10 (IL-10) cytokine escalation that was independent of glycolysis yet bolstered by apoptotic cell fatty acids and mitochondrial β-oxidation, the electron transport chain, and heightened coenzyme NAD+. Loss of IL-10 due to mitochondrial complex III defects was remarkably rescued by adding NAD+ precursors. This activated a SIRTUIN1 signaling cascade, largely independent of ATP, that culminated in activation of IL-10 transcription factor PBX1. Il-10 activation by the respiratory chain was also important in vivo, as efferocyte mitochondrial dysfunction led to cardiac rupture after myocardial injury. These findings highlight a new paradigm whereby macrophages leverage efferocytic metabolites and electron transport for anti-inflammatory reprogramming that culminates in organ repair.
    Keywords:  efferocytosis; immunometabolism; macrophage; wound healing
  5. Cancer Metastasis Rev. 2019 Jan 04.
    Thews O, Riemann A.
      Tumors often show, compared to normal tissues, a markedly decreased extracellular pH resulting from anaerobic or aerobic glycolysis in combination with a reduced removal of acidic metabolites. Several studies indicate that acidosis induces (independently from hypoxia) hematogenous and lymphatic spread of tumor cells worsening the long-term prognosis of tumor patients. This review gives an overview on the impact of low pH on different steps of metastasis including (a) local tumor cell invasion and angiogenesis, (b) intravasation of tumor cells and detachment into the circulation, and (c) adherence of circulating tumor cells, transmigration and invasion in the new host tissue. The review describes pH-dependent cellular mechanisms fostering these steps such as endothelial-to-mesenchymal transition (EMT), activation of cell migration, degradation of the extracellular matrix, or angiogenesis. The review discusses mechanisms of tumor cells for proton sensing including acid-sensitive ion channels (ASICs, TRPs) or ion transporters (NHE1) and G protein coupled H+-sensors. Finally, the review describes several intracellular signaling cascades activated by H+ sensing mechanisms leading to transcriptional, post-transcriptional, or functional changes in the cell relevant for the metastatic spread. From these studies, different therapeutical approaches are described to overcome tumor acidosis or to interfere with the signaling cascades to reduce the metastatic potential of tumors.
    Keywords:  Endothelial-to-mesenchymal transition; Intracellular signaling; Mechanisms of metastasis; Proton (H+) sensing mechanisms; Tumor acidosis
  6. Cancer Res. 2019 Jan 04. pii: canres.2545.2018. [Epub ahead of print]
    Jeong H, Kim S, Hong BJ, Lee CJ, Kim YE, Bok S, Oh JM, Gwak SH, Yoo MY, Lee MS, Chung SJ, Defrêne J, Tessier P, Pelletier M, Jeon H, Roh TY, Kim B, Kim KH, Ju JH, Kim S, Lee YJ, Kim DW, Kim IH, Kim HJ, Park JW, Lee YS, Lee JS, Cheon GJ, Weissman IL, Chung DH, Jeon YK, Ahn GO.
      Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in non-small cell lung cancer (NSCLC) patients. We found a strong correlation between CD68 TAM immunostaining and positron emission tomography (PET) 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of NSCLC patients. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 NSCLC patients from the TCGA database. TAM secreted tumor necrosis factor-α (TNF-α) to promote tumor cell glycolysis while increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies including immunotherapy.
  7. J Immunol. 2018 Dec 31. pii: ji1800637. [Epub ahead of print]
    Ren Z, Chen L, Wang Y, Wei X, Zeng S, Zheng Y, Gao C, Liu H.
      G protein-coupled receptor 120 (GPR120) has been shown to negatively regulate inflammation and apoptosis, but its role in cerebral ischemic injury remains unclear. Using an in vivo model of middle cerebral artery occlusion (MCAO) and an in vitro model of oxygen-glucose deprivation (OGD), we investigated the potential role and molecular mechanisms of GPR120 in focal cerebral ischemic injury. Increased GPR120 expression was observed in microglia and neurons following MCAO-induced ischemia in wild type C57BL/6 mice. Treatment with docosahexaenoic acid (DHA) inhibited OGD-induced inflammatory response in primary microglia and murine microglial BV2 cells, whereas silencing of GPR120 strongly exacerbated the inflammation induced by OGD and abolished the anti-inflammatory effects of DHA. Mechanistically, DHA inhibited OGD-induced inflammation through GPR120 interacting with β-arrestin2. In addition to its anti-inflammatory function, GPR120 also played a role in apoptosis as its knockdown impaired the antiapoptotic effect of DHA in OGD-induced rat pheochromocytoma (PC12) cells. Finally, using MCAO mouse model, we demonstrated that GPR120 activation protected against focal cerebral ischemic injury by preventing inflammation and apoptosis. Our study indicated that pharmacological targeting of GPR120 may provide a novel approach for the treatment of patients with ischemic stroke.